There are presently over 18 million people abusing cocaine in the US and more than 2 million heroin abusers. Combination drug use includes the "speedball" mixture of cocaine and heroin and widespread cocaine use in methadone-maintained intravenous drug users (IVDU's). Intravenous injection of cocaine and speedball mixtures, as well as lifestyles that promote high risk behaviors, renders the drug abusing population particularly vulnerable to the spread of HIV infection. A critical hypothesis for this vulnerability is the influence of drugs of abuse on disease progression. Neurobehavioral dysfunction is a significant aspect of HIV infection, neuropathology is observed in about 80-90% of AIDS patients at autopsy and virus can be measured in the cerebrospinal fluid of 50-70% of HIV infected individuals (NeuroAIDS). Direct neurotoxic effects of drugs, in addition to their effects on immunocompetence, may contribute to an enhancement of NeuroAIDS disease or accelerate its onset. Candidate mediators of neuropathogenesis include virus-derived (gp120) and host-derived (IL6, IFNalpha) factors. One experimental model involves the transgenic expression of gp120, the HIV coat protein, which has been shown to be toxic in vitro and to produce retardation of developmental milestones and spatial learning impairments in vivo. Two additional models involve the transgenic expression of the cytokines, IL6 and IFNalpha. IL6 has been shown to have a direct pathogenic role in various inflammatory, infectious, and neurodegenerative CNS diseases. The interferons are antiviral host defense molecules, and exogenous administration of IFN mimics many of the CNS symptoms of HIV infection. These transgenic mouse models exhibit unique neuropathological changes that replicate specific aspects of clinicopathology seen in NeuroAIDS. A standard procedure to study drug abuse in laboratory animals is the intravenous drug self-administration procedure. In this proposal, transgenic mice will be trained to self-administer cocaine, heroin or cocaine+heroin ("speedball") and then tested for neurobehavioral function and responsiveness to acute drug probes in tasks assessing learning (nonconditional spatial discrimination), motor activity (locomotion, catalepsy), and analgesia. Behavioral studies will be complemented by studies of molecular and cellular neuropathology and peripheral immune parameters. This research plan integrates analysis of drug effects on CNS and immune function, as relates to components of HIV disease progression, across several levels of investigation. Converging results should go far in identifying critical viral- and host-derived factors associated with increased susceptibility to the pathobiological effects of drugs of abuse and consequent synergistic neurotoxicity. Equally important, these studies will help to determine the nature of viral neuropathogenesis to specific brain systems relevant to drug reward, which may have significant clinical outcomes in terms of altered neurobehavioral and pharmacological sensitivity to drugs of abuse in HIV infected individuals.